Growth factor and inflammatory signal networks are implicated in promoting cancer development, including human head and neck squamous cell carcinomas (HNSCC). The PI3K kinases important in growth signaling are implicated in modulating the reciprocal regulation of NF-kappaB/REL oncogene and TP53/63/73 family tumor suppressor function and their role in the malignant phenotype. Our findings suggest signal regulation coordinating NF-kB, TP53, p63 and p73 interactions and function may be important in pathogenesis and as targets for prevention and therapy. Genes identified as part of the Cancer Genome Atlas Network study of head and neck cancer (Nature , 2015) are implicated in NF-kappaB and cell death pathways. Preclinical studies support combinatorial activity of Tumor Necrosis Factor (TNF) family death ligands with drugs antagonizing inhibitors of apoptosis (Eytan, Laryngoscope, 2014). Co-activation of MEK and PI3K pathways were shown to co-activate AP-1 and NF-kappaB transcription factors and contribute to resistance of HNSCC to PI3K/mTOR inhibitors (Mohan, Clin Cancer Res, 2015). PI3K/mTOR inhibitors with MEK pathway inhibitor or radiation demonstrated combinatorial activity in vitro and preclinical models in vivo.